There is no admission that the background art disclosed in this section legally constitutes prior art.
The ALL1 gene (also termed MLL) has been isolated by virtue of its involvements in recurrent chromosome translocations occurring in acute leukemias, particularly in infant acute lymphoblastic leukemias (ALL) and in therapy-related acute myeloid leukemias (11). The chromosome translocation results in the fusion of the ALL1 gene with one of more than 50 different partner genes and the production of leukemogenic proteins composed of the N-terminal All1 sequence and the C-terminus of the partner protein (11).
The Croce et al. U.S. Pat. No. 5,633,136, which is expressly incorporated herein by reference, discloses that ALL-1 polynucleotides for leukemia detection and treatment. The Croce et al. 136 provides methods for the diagnosis and treatment of human leukemias involving breakpoints on chromosome 11 in the ALL-1 locus. The ALL-1 breakpoint region, an approximately 8 kb region on chromosome 11 is also disclosed. The ALL-1 region is involved in translocations in acute lymphocytic, mylemonocytic, monocytic, and myelogenous leukemias. Probes which identify chromosome aberrations involving the ALL-1 breakpoint region on chromosome 11 are also provided. The cDNA sequence of the ALL-1 gene on chromosome 11 is provided. A partial sequence of the AF-4 gene is also provided in the context of the sequences of the two reciprocal end products of a translocation. Amino acid sequences corresponding to the cDNA sequences of the entire ALL-1 gene and the partial sequence of the AF-4 gene are also provided. Probes are provided for detecting chromosomal abnormalities involving the ALL-1 gene on chromosome 11. Monoclonal antibodies for diagnosis and treatment and antisense oligonucleotides for the treatment of acute leukemias are also described.
The Croce U.S. Pat. No. 5,567,586, which is expressly incorporated herein by reference, discloses methods of indentifying solid tumors with chromosome abnormalities in the ALL-1 region. The Croce '586 provides methods of determining whether a solid tumor has an ALL-1 gene rearrangement or an ALL-1 gene mutation. The methods comprise the steps of obtaining a sample of a solid tumor and detecting the presence of an ALL-1 gene rearrangement or mutation in a cell in said sample. ALL-1 gene rearrangements and mutations are detected by Southern blot analysis, PCR amplification analysis, in situ hybridization analysis, Northern blot analysis or DNA sequence analysis.
The Croce et al. U.S. Pat. No. 5,633,135, which is expressly incorporated herein by reference, discloses chimeric nucleic acids and proteins resulting from ALL-1 region chromosome abnormalities. The Croce et al. '135 provides methods for the diagnosis and treatment of human leukemias involving breakpoints on chromosome 11 in the ALL-1 locus. The ALL-1 breakpoint region, an approximately 8 kb region on chromosome 11, is also disclosed. The ALL-1 region is involved in translocations in acute lymphocytic, myelomonocytic, monocytic and myelogenous leukemias. Probes which identify chromosome aberrations involving the ALL-1 breakpoint region on chromosome 11 are also provided. cDNA sequences of the ALL-1 gene on chromosome 11, the AF-9 gene on chromosome 9 and the AF-4 gene, and corresponding amino acid sequences are also provided. Probes are provided for detecting chromosome abnormalities involving theses genes. Chimeric genes involved in translocations are disclosed. Monoclonal antibodies for diagnosis and treatment and antisense oligonucleotides for treatment of acute leukemias are also described.
The Croce et al. U.S. Pat. No. 6,040,140, which is expressly incorporated herein by reference, describes the cDNA sequence of the ALL-1 gene on chromosome. A partial sequence of the AF-4 gene is also provided in the context of the sequences of two reciprocal endproducts of a translocation. Amino acid sequences corresponding to the cDNA sequences of the entire ALL-1 gene and the partial sequence of the AF-4 gene, and sequences relating to chimeric genes formed by chromosome translocations with chromosome 4, 9 and 19, respectively, are also provided. Probes are also provided for detecting chromosome abnormalities involving the ALL-1 gene on chromosome 11, including probes for detecting chimeric genes generated by translocations.
The most prevalent ALL1 rearrangement in ALL is the ALL1/AF4 chimeric gene resulting from the t(4;11) chromosome translocation. This rearrangement leads to pro-B cell leukemia and is associated with very poor prognosis in infants and adults (12). The molecular pathways deregulated by A111 fusion proteins (14, 21) are only partially defined, but are likely to include process(es) involved in proliferation and differentiation of hematopoietic cells.
In spite of considerable research into therapies, ALL remains difficult to diagnose and treat effectively, and the mortality observed in patients indicates that improvements are needed in the diagnosis, treatment and prevention of the disease.